2-(2-Methyl-5-nitro-1-imidazolyl)ethyl-N-arylalkyldithiocarbamates

ABSTRACT

2-(2-Methyl-5-nitro-1-imidazolyl)ethyl esters of Narylalkyldithiocarbamates of the formula   wherein n is an integer from 1 to 7, R1 is hydrogen or lower alkyl, and R2 is hetero or carbomonocyclicaryl. These compounds are anti-microbial agents. The compounds are prepared in 2 steps. The reaction of the appropriate amine with carbon disulfide in aqueous base forms the dithiocarbamate salt and the final products are formed by the reaction of this salt with 1-(2chloroethyl)-2-methyl-5-nitroimidazole.

United States Patent [1 1 Kreider l Oct. 7, 1975 l 54 Z-(Z-METHYL-S-NITRO- l [MIDAZOLYL )ETHYL-N-ARYLALKYLDI- THIOCARBAMATES {75] Inventor: Eunice M. Kreider, Chicago, Ill.

[73] Assignee: G. D. Searle & Co., Chicago, Ill

[22] Filed: Oct. 29, 1973 [2l] Appl. No.: 410,765

Related US. Application Data [63] Continuation-impart of Ser No 294,916, Oct. 4,

1972, abandoned [52] US. Cl. 260/309; 424/273 [51] Int. Cl. t. C07D 233/94 [58] Field of Search 260/309 [56] References Cited UNITED STATES PATENTS 3.696,l l6 lO/l972 Jeanmart et al. 260/309 Primary ExaminerN0rma S. Milestone Assistant Examiner c. Mt St Jaisle Attorney, Agent, or FirmElliot N. Schubert; John J. McDonnell 571 ABSTRACT 2(2-Methyl-5-nitro-limidazolyl)ethyl esters of N-arylalkyldithiocarbamates of the formula ll Claims, N0 Drawings 2-( Z-METHYL-S-NITRO- l -IMIDAZOLYL)ETHYL- N-ARYLALKYLDITHIOCARBAMATFS This application is a continuation-in-part of my copending application Ser. No. 294,916 filed Oct. 4, I972 now abandoned The present invention relates to a group of 2-(2- methyl-S-nitro- I -imidazolyl )ethyl-N-arylalkyldithiocarbamates having the following general formula wherein n is an integer from I to 7, R is hydrogen or a lower alkyl radical, and R is a heteroor carbomonocyclicaryl radical, the latter being optionally substituted. Preferred embodiments of the present invention are those in which n is l or 2, R is hydrogen or a methyl radical, and R is phenyl, furyl or substituted phenyl. Halogens, lower alkoxy, and lower alkyl radicals are typical phenyl substituents. The preferred substitutions are 2-fluoro, 4-chloro, 3,4dichloro. 4- methoxy, 3.4-dimethoxy, and B-methyl.

The compounds of the present invention are useful in view of their anti-microbial activity. They are especially effective in inhibiting the growth of protozoa and bacteria.

Evidence of the anti-protozoal utility of the present compounds is obtained from standardized tests designed to determine the capacity of test compounds to inhibit the growth of 'I'ric/zwnonas vaginalis. These tests are carried out in the following manner. A modified Diamond medium is prepared by mixing I200 parts of trypticase (Baltimore Biological Laboratories), 600 parts of yeast extract (Difco), 300 parts of maltose, 60 parts of L-cysteine hydrochloride, 12 parts of L- ascorbic acid. 48 parts of dibasic potassium phosphate, 48 parts of monobasic potassium phosphate and 54,000 parts of distilled water. The pH is adjusted to 6.8 with 40% sodium hydroxide solution and 30 parts of agar (Baltimore Biological Laboratories) is incorporated. The mixture is boiled for one minute to dissolve the agar and is then sterilized in an autoclave. To 80 volumes of the resultant medium is aseptically added 20 volumes of sterile Dubos medium serum. The resultant medium is inoculated with 1% by volume of a 72 hour culture of Tric/mmonas vaginalz's, whereupon l ml. of the inoculated medium is mixed with IO mg. of test compound. The mixture is incubated anaerobically at 37C. for 48 hours and then examined microscopically for the presence of motile trichomonads. If any are observed the compound is considered inactive. If no motile trichomonads are observed, 0.l ml, of the incubated mixture is serially diluted and mixed wtih additional quantities of the inoculated medium sufficient to produce concentrations of I000. I00. l and l micrograms of test compound per ml. and the resulting mixtures are incubated anaerobically as before at 37C. for 48 hours and then examined microscopically for the presence of motile trichomonads. Controls are provided by concurrent incubation identical with the foregoing except for the absence of test compounds.

Further evidence of the antibacterial utility of the instant compounds is provided by standardized tests for their capacity to prevent the growth of Bacillus sublilis and Escherichia coli. In these tests, a mixture of 5 mg. of compound with 5 ml. of sterile nutrient broth is heated at 80C. for minutes, then cooled to around C., and finally serially diluted and mixed with sufficient quantities of a mixture of sterile nutrient broth and 1% of a culture of either Bacillus subrilz's or Escherichia coli to produce concentrations of approximately 400, I00, 25, and 6 mcgm. of compound per ml. The resultant mixtures are incubated for 20-24 hours at 37C. Controls are provided by concurrent incubations identical with the foregoing excepting that no compound is present. Activity is determined by gross examination; and potency is expressed as the minimum concentration, in mcgm. of compound per ml., at which no growth of the test organism is discernible.

These compounds are prepared by the general approach shown in Scheme A.

Scheme A Carbon disulfide is added to an aqueous basic solution of a given amine and the resulting dithiocarbamate salt is isolated as shown in the first step of Scheme A. Solutions of dithiocarbamate salts in polar solvents and l- (2-chloroethyl)-2-methyI-5-nitroimidazole, D. Welch and R. Vatne, J. Med. Chem., 1 I, 370, I968) are reacted in the presence of sodium or potassium iodide to form the corresponding 2-(2-methyl-5-nitrolimidazolyl )ethyl-N-arylalkyldithiocarbamates as shown in the second step of Scheme A. For instance, when carbon disulfide is added to an aqueous sodium hydroxide solution of p-chlorobenzylamine, sodium-N- p-chlorobenzyldithiocarbamate is formed and when a solution of this salt in warm dimethylformamide or dimethylsulfoxide is reacted with I-( 2-chloroethyl 2-methyl-5-nitroimidazole. 2( Z-methyI-S-nitrol imadazolyl)ethyl-N p-chlorobenzyldithiocarbamate, is

1 obtained.

amine. A solution of 4.40 parts of this salt in 25 parts EXAMPLE l by volume of warm dlmethylformamlde is reacted with To a OI II H Of 4 Parts Of Sodium hydroxide in 10 a solution of L40 parts of sodium iodide and 3.05 parts parts by volume f at is added 13 Parts Of P- of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole in 25 chlorobenzylamine. The solution is stirred in an ice parts b volume f m dime hylformamide, as debath during slow addition of IO parts by volume of carib d i E l 1 Thi pmcedure provides 2 2- bon disulfide. The reaction mixture is stirred in a cold h l-5- it -l-imidazolyl)ethyl-N-3,4- bath until a heavy precipitate results. After cooling for di h[ benzyldithiocarhamate melting at l57l58.

an additional hour, the precipitate is filtered, washed Th f l f hi Compound i with ether and vacuum dried. The resulting sodium N- p-chlorobenzyldithiocarbamate is used without further Cl purification. T

The solution of 47 parts of l-(2-chloroethyl)-2- methyl-5-nitroimidazole and 1.04 parts of sodium io- N i 2- i Cl dide in 25 parts by volume of warm 50) dimethyl l5 H form-amide is prepared and added to a solution of 6.0 parts of sodium N-p-chlorobenzyldithiocarbamate, is N CH3 prepared above, in 25 parts by volume of warm 50) dimethylformamide. The reaction mixture is stirred at room temperature under anhydrous conditions for 24 EXAMPLE 3 hours. diluted with [00 parts by volume of water and Sodium N-p-methoxybenzyldithiocarbamate is preextracted with chloroform. The chloroform solution is pared in the manner described in Example I. using an washed with water and dried over anhydrous sodium equivalent quantity of p-methoxybenzylamine as the sulfate. The sodium sulfate is filtered and the solution amine. A solution of 3.0 parts of this salt in 25 parts by is concentrated to a volume of approximately 25 parts. 25 volume of dimethylformamide is reacted with a solu- The addition of 5 parts by volume of hexane followed tion of L25 parts of sodium iodide and 2.35 parts of lby cooling provides a precipitate. The precipitate is iso- (2-chloroethyl )-2-methyl-5-nitroimidazole in 25 parts lated and dissolved in hot 50% ethyl acetate -50% hexby volume of warm dimethylformamide, as described in ane containing decolorizing charcoal. The solution is E l 1, Thi procedure id 2- 2- ;h -5- fLll'lhBl' heated and the ChZII'COill iS fillel'fid. Cooling pI'O- nitrol ethyl-N-p-methgxybenzyldithiocarvide rystal f I y -ni ml -im lyl) thylbamate, melting at l52-l 53. The formula for this N-p-chlorobenzyldithiocarbamate. melting at m o nd i S ll NCH2CH2S N-CH o cH.,

H N H-i l38.5l 39. The formula of this compound is EXAMPLE 4 N02 Sodium N-3,4-dimethoxybenzyldithiocarbamate is prepared in the manner described in Example 1, using an equivalent quantity of 3,4-dimetl1oxybenzylamine as the amine. A solution of 5.30 parts of this salt in 25 {J H parts by volume of warm dimethylformamide is reacted u with a solution of 1.74 parts of sodium iodide and 3.78 parts of l-( 2-chloroethyl )-2-methyl-5-nitroimidazole in 25 parts by volume of warm dimethylformamide, as described in Example 1. This procedure provides 2-(2- methyl-S-nitrol -imidazolyl )ethyl-N-3 .4-

EXAMPLE 2 Sodium N-3,4-dichlorobenzyldithiocarbamate is prepared in the manner described in Example 1, using an 55 dimethoxybenzyldithiocarbamate, melting at equivalent quantity of 3,4-dichlorobenzylamine as the l l6l l7. The formula for this compound is s ll N H. CH:-S-Cl|\l-(H 0 i1 H i N EXAMPLE 5 Sodium N-o-fluorobenzyldithiocarbamate is prepared in the manner described in Example I. using an equivalent quantity of o-fluorobenzylamine as the amine. A solution of 3.12 parts of this salt in 25 parts by volume of warm dimethylformamide is reacted with a solution of L5 parts of sodium iodide and 2.27 parts of l-(2-chloroethyl)-2-methylformamide. as described in Example 1, This procedure provides 2-( Z-methyI-S' nitrol -imida2olyl )ethyl-N-o-fluorobenzyldithiocarbamate melting at l33.5l34.5. The formula for this compound is EXAMPLE 6 Sodium N-m-methylbenzyldithiocarbamate is prepared in the manner described in Example I, using an equivalent quantity of m-methylbenzylamine as the amine. A solution of 2.96 parts of this salt in 25 parts by volume of warm dimethylformamide is reacted with a solution of L5 parts of sodium iodide and 2.27 parts of l-(Z-chloroethyl)-2-methyl-5-nitroimidazole in 25 parts by volume of warm dimethylformamide, as described in Example 1. This procedure provides 2-(2- methyl-S-nitro-1-imidazolyl)ethyl-N-mmethylbenzyldithiocarbamate, melting at l-122. The formula for this compound is 5 l N cH, cH, s- TCH,,

/ H N C 3 ca.

EXAMPLE 7 Sodium N-furfuryldithiocarbamate is prepared in the manner described in Example 1, using an equivalent quantity of furfurylamine as the amine. A solution of 3.90 parts of this salt in parts by volume of warm dimethylformamidc is reacted with a solution of 1.70 parts of sodium iodide and 3.78 parts of l-(2- chloroethyl)-Z-methyI-S-nitroimidazole in 25 parts by volume of warm dimethylformamide, as described in Example. This procedure provides 2-(2-methyl-5-nitrol-imidazolyl )ethyl-N-furfuryldithiocarbamate, melting at l59l6(). The formula for this compound is EXAMPLE 8 Sodium N-p-chlorophenethyldithiocarbamate is prepared in the manner described in Example I, using an equivalent quantity of p-chlorophenethylamine as the amine. A solution of 3.65 parts of this salt in 25 parts by volume of warm dimethylformamide is reacted with a solution of 1.25 parts of sodium iodide and 2.73 parts of l-( 2-chloroethyl)-2-methyl-5-nitroimidazole in 25 parts by volume of warm dimethylformamide, as described in Example 1. This procedure provides 2-( 2- methyl-S-nitrol -imidazolyl )ethyl-N-pchlorophenethyldithiocarbamate, melting l56l56.5. The formula for this compound is EXAMPLE 9 ilt EXAMPLE Sodium N-methylbenzyldithiocarbamate is prepared in the manner described in Example 1, using an equivalent quantity of N-methylbenzylamine as the amine. A solution of 4.38 parts of this salt in parts by volume of warm diemthylformamide is reacted a solution of 1.72 parts of sodium iodide and 3.78 parts of 1-(2- chloroethyl)-2-methyl-5-nitroimidazole in 25 parts by volume of wami dimethylformamide, as described in 10 thiocarbamate. The formula for this compound is Example l. This procedure provides 2-(2-methyl-5- nitrol -imidazolyl )ethyl-N-methyl-N-benzyldithiocarbamate, melting at 124l25. The formula for this compound is Sodium N-n-propyLN-benzyldithiocarbamate is prepared in the manner described in Example 1, using an equivalent quantity of N-propylbenzylamine the amine. A solution of 4.38 parts of this salt in 25 parts by volume of warm dimethylformamide is reacted with a solution of 1.72 parts of sodium iodide and 3.78 parts of l-( 2-ch1oroethyl)-2-methyl-5-nitroimidazole in 25 parts by volume of warm dimethylformamide, as described in Example 1. This procedure provides 2- (2methyl-5-nitrol -imidazolyl )ethyl-N-n-propyl-N- benzyldithiocarbamate. The formula for this com- EXAMPLE 12 Sodium N-p-ethoxybenzyldithiocarbamate is pre- EXAMPLE 1 3 Sodium N-p-n-butylbenzyldithiocarbamate is prepared in the manner described in Example 1, using an equivalent quantity of p-n-butylbenzylamine as the amine. A solution of 3.2 parts of this salt in 25 parts by volume of warm dimethylformamide is reacted with a solution of 1.4 parts of sodium iodide and 2.6 parts of l-(2-chloroethyl)-2-methy1-5-nitroimidazole in 25 parts by volume of warm dimethylformamide, as described in Example 1. This procedure provides 2-(2- methyl-5-nitro-imidazolyl )ethyl-N-p-butylbenzyldithiocarbamate. The formula for this compound is NO, S

N l R wherein n is a positive integer from 1 to 7, R, is hydrogen or lower alkyl, and R is phenyl. furyl or halophenyl containing 1 or 2 halo. (lower alkoxy)phenyl containing 1 or 2 lower alkoxy. or (lower alkyl)phenyl containing 1 lower alkyl.

2. According to claim 1, the compound which is 2- (2methyl-S-nitro-S-nitro-1 imidazolyl)ethyl-N-3.4- dichlorobenzyldithiocarbamate.

3. According to claim I, the compound which is 2-( 2- methyl- S-nitrol -imidazolyl )ethyl-N-p-chlorobenzyldithiocarbamate.

4. According to claim 1, the compound which is 2-( 2- mcthyl-Smitrol -imidazolyl )ethyl-N-pmcthoxybenzyldithiocarbamate.

5. According to claim 1, the compound which is 2-( 2' 9. According to claim I, the compound which is 2-( 2- methyl-S-nitrol -imidaz0lyl )ethyl-N-pchlorophcnethyldithiocarbamate.

10. According to claim 1, the compound which is 2- (2-methyl-5-nitro-2-imidazolyl )ethyl-N-pmethoxyphenethyldithiocarbamate.

11. According to claim 1, the compound which is 2- (Z-methyl-S-nitrol-imidazolyl )ethyl-N-methyl-N- benzyldithiocarbamate.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,910,9 5 DATED Oct. 7, 1975 INVENTORtS) Eunice E-t. Kreider' It ts certrtred that error appears m the ab0verdentifted patent and that said Letters Patent are hereby corrected as shown betow:

Column 2, line 50, "limidazolvl)" should read l-imidazolyl) Column 5, line 9, after "-2-" insert "methyl-5- nitr-oimidazole in 25 parts by volume of warm d1".

Column Claim 2, line 59, "(2methyl5nitro5nitro" (2-methvl-5-nitro Column 8, should read Column 10, Claim 10, line 5, unitro 2u Shculd read nitro-l Signed and fizzled this seventeenth Day Of February 1976 [SEAL] Arrest:

C. MARSHALL DANN Arresting Officer 7, line 53, (2mechyl" should read (2-methyl 

1. A COMPOUND OF THE FORMULA
 2. According to claim 1, the compound which is 2-(2methyl-5-nitro-5-nitro-1-imidazolyl)ethyl-N-3,4 -dichlorobenzyldithiocarbamate.
 3. According to claim 1, the compound which is 2-(2-methyl-5-nitro-1-imidazolyl)ethyl-N-p-chlorobenzyldithiocarbamate.
 4. According to claim 1, the compound which is 2-(2-methyl-5-nitro-1-imidazolyl)ethyl-N-p-methoxybenzyldithiocarbamate.
 5. According to claim 1, the compound which is 2-(2-methyl-5-nitro-1-imidazolyl)ethyl-N-3,4-dimethoxybenzyldithiocarbamate.
 6. According to claim 1, the compound which is 2-(2-methyl-5-nitro-1-imidazolyl)ethyl-N-o-fluorobenzyldithiocarbamate.
 7. According to claim 1, the compound which is 2-(2-methyl-5-nitro-1-imidazolyl)ethyl-N-m-methylbenzyldithiocarbamate.
 8. According to claim 1, the compound which is 2-(2-methyl-5-nitro-1-imidazolyl)ethyl-N-furfuryldithiocarbamate.
 9. According to claim 1, the compound which is 2-(2-methyl-5-nitro-1-imidazolyl)ethyl-N-p-chlorophenethyldithiocarbamate.
 10. According to claim 1, the compound which is 2-(2-methyl-5-nitro-2-imidazolyl)ethyl-N-p-methoxyphenethyldithiocarbamate.
 11. According to claim 1, the compound which is 2-(2-methyl-5-nitro-1-imidazolyl)ethyl-N-methyl-N-benzyldithiocarbamate. 